PROJECT SUMMARY Depression is a chronic and debilitating mental illness. Anhedonia, one of the two core symptoms of major depression, is particularly difficult to treat. Individuals can experience one or more types of anhedonia, defined as a loss of interest or a loss of pleasure. However, the neural circuits and molecular substrates underlying anhedonia and other key depressive symptoms remain poorly understood. The arcuate nucleus (ARC) of the hypothalamus contains two distinct neuronal populations expressing proopiomelanocortin (POMC) and agouti-related protein (AgRP) that are well known for their roles in homeostatic and hedonic control of feeding. We demonstrated that chronic unpredictable stress causes different types of anhedonia and behavioral despair and induces opposite changes in spontaneous firing rate of POMC and AgRP neurons. We hypothesize that POMC and AgRP neurons play distinct roles in chronic stress-induced depressive behaviors. The specific aims of this project are designed to determine 1) how chronic unpredictable stress regulates POMC and AgRP neuronal activity; 2) whether SIRT1 in POMC and AgRP neurons functions as a molecular mediator of chronic stress-induced depressive behaviors and neuronal dysfunction; and 3) whether selective activation or inhibition of POMC and AgRP neurons causes or reverses depressive behaviors.